Lewy body disease (LBD) is a group of disorders characterized by alpha-synuclein (a-syn) accumulation and Parkinsonism. During the previous period, the objective was to understand the mechanisms by which alpha- synuclein (a-syn) a close homologue to a-syn blocks a-syn aggregation and might have a role in the treatment of degenerative disorders such as Alzheimer's disease (AD) and LBD. Both p-syn and antibodies against a-syn target a-syn aggregates for clearance probably via autophagy, a process of degradation and recycling of cellular constituents. Alterations in autophagy might play a role in the pathogenesis of AD and LBD, and might represent a target for treatment development. The objectives of this renewal application are: i) to gain new knowledge as to the involvement of the autophagy pathways in the mechanisms of neurodegeneration in LBD, ii) to develop new experimental therapies for LBD by targeting the autophagy pathways and iii) to better understand the involvement of the autophagy pathways in the mechanisms of a- syn clearance mediated by immunotherapy. We propose the following Aims: AIM 1. Characterize in vivo the contribution of selected molecular components of the autophagy pathway to the pathogenesis of LBD. AIM 2. Investigate in in vivo models of alpha-synucleinopathy the therapeutic and neuroprotective effects of activators of the autophagy pathway. AIM 3. Better understand the cellular mechanisms involved in the clearance of toxic a-syn aggregates via specific antibodies. AIM 4. Determine in immunized animals, the contribution of autophagy to the molecular mechanisms involved in a-syn clearance. a-Syn transgenic mice will be crossed with mice either deficient in or transgenic for components of the autophagy pathway (e.g. Beclinl, LAMP2, mTor). Mice will be treated with stimulators of autophagy (rapamycin, immunotherapy) and analyzed behaviorally, biochemically and neuropathologically. Studies will be complemented with primary neuronal cultures treated with lentiviral vectors and analyzed for markers of autophagy. Better understanding the autophagic pathways involved in a-syn clearance is of central importance toward elucidating the pathogenesis of LBD and developing new treatments for these conditions. Thus, enhancing autophagy and lysosomal degradation of a-syn may represent a promising therapeutic strategy for the treatment not only for LBD but also for Alzheimer's disease.